The adrenergic receptors (ARs), through which norepinephrine and epinephrine exert their biological activities, are targets for many therapeutically important drugs. The α1-ARs play a dominant role in control of smooth muscle contraction and are important in control of blood pressure, nasal congestion, prostate function, and other processes (Harrison et al., Trends Pharmacol Sci; 1991; 62-67). The α1-ARs were originally classified by pharmacological profiling into two subtypes, α1a and α1b (Morrow and Creese, Mol. Pharmacol; 1986; 29: 231-330; Minneman et al., Mol. Pharmacol; 1988; 33:509-514). Three genes encoding different α1-AR subtypes (α1a, α1b, and α1d) have been cloned for a number of species, including human (Schwinn et al., J. Biol Chem; 1990; 265: 8183-8189; Ramarao et al., J Biol Chem; 1992; 267:21936-21945; Bruno et al., Biochem Biophys Res Commun; 1991; 179: 1485-1490). These three cloned α1-ARs are best differentiated from one another on the basis of the relative binding affinities of a series of antagonist compounds. There is general agreement that the α1a- and α1b-ARs correspond to the pharmacologically defined α1a- and α1b-ARs, while the functional role of the α1d-AR is less clear, although it appears to mediate contraction of certain blood vessels (Goetz et al., Eur J Pharmacol; 1991; 272:R5-R6). Like other ARs, the α1-ARs are members of the G-protein coupled receptor super family, and in most cells the primary functional response to activation of all α1-AR subtypes is an increase in intracellular Ca2+.
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate and is the cause of lower urinary tract symptoms (LUTS) in a large segment of the elderly male population. Symptoms such as straining, hesitancy, dribbling, weak stream, and incomplete emptying are classified as voiding or obstructive symptoms. Obstructive symptoms are primarily due to pressure upon the urethra from the physical mass of the enlarged prostate gland (the static component) and the increased tone of the smooth muscle of the prostate stroma and bladder neck (the dynamic component) (Caine, J Urol; 1986; 136: 1-4). Irritative or storage symptoms associated with BPH are frequency, urgency, nocturia, dysuria, and burning sensation. Patients feel that these symptoms are more disturbing than the obstructive symptoms. As the urine flow is reduced, due to the bladder outlet obstruction, the wall around the bladder base thickens and becomes hyperactive.
Functional studies have established that prostate smooth muscle tone is maintained through α1-ARs and that these receptors mediate the dynamic component of obstruction. α1-AR antagonists have successfully been used to treat the obstructive symptoms associated with BPH (Jardin et al., Scientific Communications Int; 1998; pp 559-632). Furthermore, the α1a-AR subtype comprises the majority of α1a-ARs in human prostatic smooth muscle and has been shown to mediate contraction in this tissue. Originally introduced as antihypertensive agents, α1-AR antagonists have become increasingly important in the management of BPH. α1-AR antagonists reduce smooth muscle tone in the prostate and lower urinary tract, thereby relaxing the bladder outlet and increasing urinary flow. The major disadvantage of non-selective α1-blockers is their adverse effect profile, particularly vasodilatation leading to dizziness, postural hypotension, asthenia, and occasionally syncope. For this reason, it would be desirable to block α1-ARs in the lower urinary tract without antagonizing the α1-ARs responsible for maintaining vascular tone.
A number of factors can be involved in lower urinary tract symptoms. Adrenergic stimulation of the bladder results in relaxation due to β-ARs, which dominate over contraction-mediating α1-ARs. Bladder contraction is primarily mediated by muscarinic receptors. Some studies indicate that the contribution from α1-ARs increases in hyperactive bladders due to bladder outlet obstruction or other conditions (Perlberg et al., Urology; 1982; 20:524-527); Restorick and Mundy, Br J Urol; 1989; 63: 32-35). However another study finds no change in α1-AR receptor function between normal and hypertrophic bladder due to outlet obstruction (Smith and Chapple, Neurolog Urodyn; 1994; 12: 414-415). It remains unclear, which α1-AR is dominant in the human bladder. One study reported a predominance of the α1a subtype mRNA in the bladder dome, base, and trigone (Walden et al., J Urol; 1997; 157: 414-415). Another report found that the α1d subtype is present as 66% of the α1-ARs at both the mRNA and protein levels, while the α1a subtype is present as 34% of the total, with no evidence of the α1b subtype (Malloy et al., J Urol; 1998; 160: 937-943). Drugs that selectively antagonize only the α1a-AR subtype appear to have little effect upon the irritative symptoms of BPH. Ro-70004, a α1a subtype-selective compound was reported to be discontinued in clinical studies when it was found to have poor efficacy in treating these symptoms (Blue et al., Abstract 5th International Consultation on BPH (Jun. 25-28) 2000). α1d-ARs may be involved in mediating the irritative symptoms; however, the location of these α1d-ARs is unknown (Piascik and Perez, J Pharmacol Exp Ther; 2001; 298: 403-410).
Studies have demonstrated Central Nervous Systems (CNS) inhibitory effects of α1 antagonists upon the sympathetic and somatic outflow to the bladder in cats (Danuser and Thor, J Urol; 1995; 153: 1308-1312; Ramage and Wyllie, Eur J Pharmacol; 1995; 294: 645-650). Intrathecafly administered doxazosin caused a decrease in micturition pressure in both normal rats and rats with bladder hypertrophy secondary to outlet obstruction (Ishizuka et al., Br J Pharmacol; 1996; 117:962-966). These effects may be due to a reduction in parasympathetic nerve activity in the spinal cord and ganglia. Other studies used spontaneously hypertensive rats, which have overactive bladders, to demonstrate that α1-AR antagonism only given intrathecally caused a return to normal micturition (Persson et al., Am J Physiol; 1998; 275:R1366-1373, Steers et al. 1999; Exp Physiol; 84:137-147.). Antagonists administered intra-arterially near the bladder, or ablation of peripheral noradrenergic nerves, had no effect upon the bladder overactivity in these animals, indicating that α1-ARs in the spinal cord control the bladder activity. Spinal α1-ARs may be important targets for pharmacological treatment of BPH symptoms in humans as well. All three α1-AR subtype mRNAs are found throughout the human spinal cord, however the aid subtype mRNA is present at twice the level of the other subtypes, particularly in the ventral sacral motor neurons and autonomic parasympathetic pathways. (Stafford-Smith et al., Mol Brain Res; 1998; 63:234-261). There may be clinical advantages to the pharmacological blockade of the α1d-ARs in the CNS in reducing BPH symptoms.
Antagonism of α1d-ARs in the CNS and bladder may be an important activity in reducing the irritative or filling symptoms of BPH and improving patient symptom scores. Tamsulosin (Flomax®, Yamanuchi and Boehringer Ingelheim) is a α1-AR antagonist, which is about 15-fold selective for the α1a and α1d subtypes over the α1b subtype. Large clinical trials of BPH patients with tamsulosin showed improvement in both obstructive and irritative symptoms, however, cardiovascular and erectile dysfunction side effects were seen (Abrams et al. Br J Urol; 1995; 76:325-336; Chapple et al., Eur Urol; 1996; 29:155-167; Lepor, Urology; 1998; 51:892-900). Patients treated with non-selective α1 antagonists also have improvement in both obstructive and irritative symptoms, although the risk of vascular side effects is greater. Generally, the α1a subtype predominates in arteries at the mRNA and protein levels, while all three subtypes are found in veins. The particular vessel bed is important in that the α1a is the subtype found primarily in the splanchnic and coronary arteries, while the α1d subtype is the predominant subtype found in the aorta. The α1-AR subtypes in the vasculature have been found to change with age. Contraction of the mammary artery is mediated by both α1a and α1b subtypes. The number of al receptors in the mammary artery doubles with age; however, the α1b subtype increases to a greater extent than the α1a subtype (Raudner et al., Circulation; 1999; 100:2336-2343). The α1b subtype may play a greater role in vascular tone in elderly patients. This suggests that an α1a and α1d-selective antagonist may have less effects upon the vasculature in elderly BPH patients, resulting in fewer cardiovascular side effects than are seen with non-selective α1 antagonists, but provide relief from both obstructive and irritative symptoms.
A uroselective, cardiovascular-sparing α1-AR antagonist would be expected to provide symptomatic relief of BPH comparable to currently marketed non-selective agents such as terazosin/Hytrin®, doxazosin/Cardura®, alfuzosin/Xatral®/Uroxatral® and weakly selective tamsulosin/Flomax®/Harnal®, without the undesirable side effects of postural hypotension, dizziness, and syncope. Ejaculatory dysfunction, or retrograde ejaculation, is a side effect seen in 10 to 35% of patients using tamsulosin (Lepor, Urology; 1998; 51:901-906; Andersson and Wyllie, Brit J Urol Int; 2003; 92:876-877). This activity has been attributed to tamsulosin antagonism at the 5-HT1a receptor. This often leads to discontinuation of treatment. Furthermore, the non-selective α1-AR antagonists and tamsulosin are contraindicated for use in conjunction with PDE inhibitors. There is likely to be high co-morbidity between LUTS and erectile dysfunction patients. Patients being treated for LUTS with the current α1-AR blockers will find that they are excluded from using PDE inhibitors. An α1-AR antagonist with a receptor subtype binding profile, which is selective for the α1a and α1d, subtypes, but with relatively little antagonism of the α1b subtype may effectively treat both obstructive and irritative symptoms of BPH. Such a compound is likely to have a low cardiovascular side effect profile and allow for use in conjunction with PDE inhibitors. Also low binding activity at the 5-HT1a receptor is likely to reduce the incidence of ejaculatory side effects.
LUTS also develop in women of a certain age. As in men, LUTS in women include both filling symptoms such as urgency, incontinence and nocturnia, and voiding symptoms such as weak stream, hesitancy, incomplete bladder emptying and abdominal straining. The presence of this condition both in men and women suggests that at least part of the aetiology may be similar in the two sexes.
Accordingly, there is a need to provide α1a/α1d adrenoreceptor modulator compounds; in particular, mono or dual selective α1a/α1d adrenoreceptor modulator compounds; more particularly, mono or dual selective α1a/α1d adrenoreceptor antagonist compounds, in other words compounds that interact with either one (i.e., “mono”) or both (i.e., “dual”) the α1a or/and α1d adrenoreceptor but do not interact (or at least interact substantially less) with the α1b adrenoreceptor. The compounds of this invention are believed to be more efficacious drugs mainly for BPH/LUTS patients, and at the same time these compounds should show less unwanted side effects than the existing pharmaceuticals.